CN1805948A - Stabilized derivatives of ascorbic acid. - Google Patents

Stabilized derivatives of ascorbic acid. Download PDF

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CN1805948A
CN1805948A CNA2004800165028A CN200480016502A CN1805948A CN 1805948 A CN1805948 A CN 1805948A CN A2004800165028 A CNA2004800165028 A CN A2004800165028A CN 200480016502 A CN200480016502 A CN 200480016502A CN 1805948 A CN1805948 A CN 1805948A
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acid
compound
xitix
skin
cosmetic composition
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E·克维特尼斯基
V·贝拉克霍夫
V·巴特索夫
Y·沙皮罗
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Tagra Biotechnologies Ltd
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/62—Three oxygen atoms, e.g. ascorbic acid
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
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    • A61K8/676—Ascorbic acid, i.e. vitamin C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

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Abstract

Ascorbic acid derivatives of the general formula 1: wherein R<1> is a C2-C22 acyl group, an amino acid group, or a C1-C17 alkyl group; R<2> is ammonium or a metal cation; and each of R<3> or R<4>, independently, is hydrogen, a C2-C22 acyl group, an amino acid residue, or a C1-C17 alkyl group, are more stable than ascorbic acid and can be used as a source of vitamin C in pharmaceutical, nutraceutical and cosmetic compositions.

Description

The stable derivatives of xitix
Invention field
The present invention relates to novel stable ascorbic acid derivates and the composition that comprises this derivative.
Background of invention
Vitamins C (xitix) is people's important nutrient substance and many important function is arranged in vivo.Vitamins C is synthetic for collagen to be essential and to help to keep the integrity that a matter produces material, for example reticular tissue, osteoid and a dentine.A critical function of xitix is to act on the proline(Pro) of major protein composition collagen in the body and the hydroxylation of lysine residue as cofactor, and this skin elasticity and structure for maintaining healthy is important.The recovery that xitix is also very important to wound healing and promotion is burnt.As potent reductive agent, xitix is reversibility oxidation and reduction in vivo, plays redox system and help the treatment of cancer in cell.Vitamins C relates to the metabolism of phenylalanine and tyrosine.Vitamins C promotes that the absorption of iron and protection conversion folic acid are the folic acid reductase of formyl tetrahydrofolic acid, and the folic acid that can help to dissociate in the food discharges from its conjugate.
Vitamins C is a kind of potent antioxidant, and protection DNA, membrane lipid and protein are avoided oxidative damage.As mentioned above, vitamins C relates to for example collagen synthetic of numerous materials, also relates to synthetic and neural mediator, the lipid, proteinic synthetic of some anabolic steroid hormone.Seeming suitable immunologic function needs vitamins C and suggestion to be used for prevention or treatment flu.As if though not studies have shown that by experiment, vitamins C has reduced or has reduced the seriousness of flu.
Vitamins C also is an antioxidant in a kind of water-soluble cell, in intracellular fluid and intercellular fluid and free radical reaction, and after free radical reaction exhausts vitamin-E, thus can be by regeneration " recovery " vitamin-E chemically.
Use the activeconstituents of vitamins C in recent years as makeup.Because its antioxidation property considers that vitamins C is given antioxidant and photoprotection makes skin avoid free radical attack and UV phototoxis.Since think that free radical causes skin lesion and crosses presenility, now the makeup that contain the vitamins C or derivatives thereof are sold as antidotal agent, be used for preventing the skin free radical damage due to the UVA ray, and generation renewal skin elasticity and soundness by collagen, iuntercellular dental cement (cement) and other underworks.
Hypovitaminosis C causes vitamin C deficiency, it is characterized in that capillary fragility causes damaging and lax, the anaemia of hemorrhage, gum inflammation, tooth and can cause dead general weakness.In some cases, can advise that medication person improves the vitamins C amount, for example for using oestrogenic hormon, oral contraceptive, barbiturate, tsiklomitsin, the people of acetylsalicylic acid and the people of smoking.
Many fruits and vegetables contain vitamins C.Yet for guaranteeing enough amounts of diet, suggestion provides additional vitamins C.
Yet, pure vitamin C is mixed with end product has serious difficulty, because it is easily oxidized.The storage or be exposed under light, oxygen, moisture and/or the high temperature, vitamins C is degraded rapidly.Vitamins C instability in the aqueous solution even under neutral pH and the room temperature.Its also with for example molysite and the mantoquita reaction of some mineral substance, cause degrading more rapidly.
In order to overcome xitix stable insufficient problem under its respective pure form, the derivative of more stable it has been proposed.According to a kind of method, stable xitix and its hydrophobic derivatives have been obtained after being embedded into cyclodextrin, zeolite or liposome.
Another kind method obtains stablizing xitix by its enediol (enediol) functional group derivatization.The xitix of lactone form has 4 hydroxyls on carbon 2,3,5 and 6.These hydroxyls have different chemically reactives: the 2-hydroxyl has formed an enediol system with the 3-hydroxyl with the two keys that are connected carbon 2 and carbon 3, very responsive and cause the oxidative degradation of xitix to oxygenizement, however 5-hydroxyl and 6-hydroxyl have formed dibasic alcohol (diol) system of quite stable.The derivatize of xitix is converted to the group that contains alkyl, acyl group, sulfo-or phosphoryl to hydroxyl usually, and derivatization also influences the solubleness of xitix in water or oil.Known ascorbic acid derivates is divided into two big class, water-soluble ascorbic acid derivates and oil soluble ascorbic acid derivates.This two analog derivative has different potential uses.
Attempt preparation L-xitix 2-phosphoric acid ester or L-xitix 2-sulfuric ester and stablize xitix through its 2-position enediol functional group derivatization.Xitix 2-phosphate derivative shows some biological activitys, but xitix 2-sulfuric ester does not find to become effective biological agent.
In recent years, adopt important step that VITAMIN and other promoting agents are introduced dermatological compositions or cosmetic composition.Especially consider ascorbic dermatology and cosmetic use.By stimulating and regulating the synthetic of collagen, vitamins C is promoted the elasticity and the structural integrity of people's skin, and suppresses the formation of wrinkle.Another important benefits of xitix is that it makes skin avoid the provide protection of oxidative damage.A major reason of damaging on the skin is the generation by reactive oxygen intermediate (reactive oxygen species) due to chemical pollutant, smoking, especially ultraviolet ray (UV) ray.Reactive oxygen intermediate can damage lipid in the skin cells, protein and nucleic acid, then can cause the generation of skin carcinoma and photoaging.Numerous investigators report that high-caliber xitix in the skin that the topical application of VITAMIN produces provides the protection to UV ray part degree, especially to UVA (Darr, D., S Dunston, H.Faust and S.Pinnell.1996.Acta Derm.Venereol. (Stockh) .76:264-268; Black H.S., and J.T.Chan.1975.J.Invest.Dermatol.65:412-414).This provide protection obviously is owing to removed the oxyradical that produces in the cytosol due to the UVA ray.
Therefore, comprise ascorbic topical composition and can be used for the various skin problems of specific treatment, for example aging, dry, acne or pigmentation disorder.As long as set up in the tissue and keep high-caliber vitamins C, the effect that the useful effect of the xitix of topical application, especially its antioxidant activity produce is optimistic.(Uacques, P.F., and L.T.Chylack.1991.Am.J.Clin.Nutr.53:352S-355S).Because active transport mechanism is regulated and the vitamins C concentration of restriction skin, the increase of vitamins C picked-up does not cause the increase (Rumsey, S.C., and M.Levine.1998.J.Nutr.Biochem.9:116-130) of xitix level in the skin.Can increase gathering of protectiveness antioxidant effectively and increase collagen synthetic although the xitix of directly sending high density through stratum corneum barrier enters skin, must overcome many obstacles to reach this target.For example, water miscible vitamins C good preservation and promptly excreting not in tissue, in human body half life be about 20 days (Ritchey, S.J.1965.Am.J.Clin.Nutr.17:57-114).Equally, because ascorbic wetting ability, it is not advanced specific tissue by good absorption, the especially natural resistance water and the skin of water-soluble substances.The xitix of topical application relies on carrier about only 8% and is really absorbed (Darr, D., S.Combs, S.Dunston, T.Manning, and S.Pinnell.1991.J.Invest.Dermatol.96:590) by skin.Nature, contain the strength protection of vitamins C acquisition in many compositions to antioxygenation.Can obtain the form that vitamin C derivatives is applicable to any skin type, but key is to use the really stable form of transdermal acquisition protectiveness antioxidant effect.
In the stable derivatives that in topical formulations, uses, can find 6-Quicifal (ascorbyl palmitate), a kind of bioavailability height of xitix, fat-soluble derivant, have vitamins C and have superiority, but do not resemble water-soluble form but can in the lipid cytolemma, store up to being utilized by body.Another known vitamin C derivatives is L-xitix-2-trimagnesium phosphate (MAP), a kind of water-soluble, stable, nontoxic non-irritating derivative, be used for the modern functions whitening cosmetic as additive, declare by the active spot of removing of restraint of tyrosinase, by eliminating the oxygen radical removing wrinkle after the skin absorption, and synergy is arranged with vitamin-E.
Diluted sample is after suitable water-organic solvent mixture, and directly RP-HPLC analyses and investigates the stability of xitix, Quicifal and xitix-2-trimagnesium phosphate in standardized solution and the topical formulations.Though the result shows that these two kinds of vitamin C derivatives are more stable than xitix, acid ascorbyl ester demonstrates marked difference.Do not stop in the solution with the palmitinic acid esterification or the hydrolysis of molecule in the emulsion at 6.Have only the product of the high viscous-elastic behaviour of special preparation can reduce the typical behavior of this compound.Opposite; 2 introduce the phosphoric acid radical protections molecule fracture of enediol system does not take place; having proved conclusively xitix-2-trimagnesium phosphate is the highly stable derivative of vitamins C, can successfully be used for all types of cosmetic products (Austria, R.; Semenzato; A., Bettero, A.Stability of vitamin C derivativesin solution and topical formulations.J.Pharm.Biomed.Anal.1997; 15 (6), 795-801).
US 5,098, and 898 have described glyceryl ester or glyceryl ether is connected to the L-xitix via the phosphoric acid residue.It is active that antioxidant activity that the gained compound exhibits is good and lipid peroxide suppress.Yet the enediol system does not protect fully also thereby not can be used as the vitamins C source and is used for topical formulations.
JP 63104971 and DE 3613590 disclose 2,3-two-O-acyl group L-xitix synthetic, and it is more fast light than aforementioned phosphorylation L-xitix., because this product solubleness in water is low, 2,3-two-O-acidylate causes the reduction of bioactive forfeiture and bioavailability.Therefore, such compound is almost useless for makeup, dermatological applications and other application.
JP 7017989, JP 8034791, JP 98363316 and JP 98201242 disclose the application in the anti-dandruff and skin whitening composition at chemistry of L-xitix 2-phosphoric acid, with prevention reagent skin permeation depths and reduce hormesis to skin.The 2-phosphoric acid ester that contains the L-ascorbic acid derivates shows adequate stability and has kept the inherent activity.
US 3,671,549 and DE 1805958 disclose with Phosphorates phosphorus Halides, phosphoric acid or halophosphoric acid or their corresponding acid anhydrides by the synthetic L-xitix of the direct phosphorylation of xitix-3-phosphoric acid.This process is suitable for scale operation.
JP 10324627 discloses the synthetic of the L-ascorbic acid derivates that is used as antitumour drug, its 2 have phosphate radical, pyrophosphate, triphosphate, multi-phosphate, sulfate radical or glycosyl, and 3 have hydroxyl, phosphate radical, multi-phosphate, sulfate radical, glycosyl, alkoxyl group, alkene oxygen base or phenoxy group.Because the target of this patent is not stability problem but new pharmacological activity, thus 2 of no usely be enough to protect the two not oxidated residues of key of enediol to carry out O-to replace.
US 5,516,919 have described the production method of the metal-salt or the optional ammonium salt that replaces of ascorbic acid derivates, with the porous sorbent material for example activated carbon treatment contain the acidic aqueous solution of xitix 2-phosphoric acid ester or xitix 2-sulfuric ester, then handle this sorbent material with the ammonium salt ion or the unsubstituted ammonium salt ionic alkaline aqueous solution that contain for example organic acid metal-salt, replacement, thereby by simply also being easy to the finished product that operation obtains high-yield high-quality.
US 6,110,477 disclose the topical composition of the skin that is used to prevent and/or treat photoaging, sunburn, wrinkle and relevant skin disorder, and said composition is included in xitix in the pharmaceutically acceptable matrix of anhydrous basically single-phase vehicles or its derivative.Disclosed this ascorbic acid derivates is Quicifal, sodium ascorbate, potassium ascorbate, xitix ammonium, xitix trolamine, ascorbic acid phosphoric acid esters or magnesium ascorbyl phosphate.
US 6,602, and 906 disclose and are used for 5 of local skin treatment, and the purposes of 6-O-isopropylidene-L-xitix is used for improving the skin corium ascorbic acid concentrations of skin, and it is synthetic and improve the antioxidant potentiality of skin to increase skin collagen.
Summary of the invention
A target of the present invention provides stable ascorbic acid derivates, and is more stable than vitamin c itself basically during storage period.
The present invention relates to the compound of general formula (I):
Figure A20048001650200101
R wherein 1Be C 2-C 22Acyl group, amino-acid residue or C 1-C 17Alkyl; R 2Be ammonium or metallic cation; R 3Or R 4Independent separately is hydrogen, C 2-C 22Acyl group, amino-acid residue or C 1-C 17Alkyl.
The present invention further provides the method for the compound of preparation formula (I).
The present invention further provides and comprises formula (I) compound compositions.
Detailed Description Of The Invention
The compound of formula of the present invention (I) is to compare more stable ascorbic acid derivates with xitix.Derivatize had protected 2 when the stability of these derivatives came from 2-hydroxyl and 3-hydroxyl, this fact of 3-enediol system.
The ascorbic acid derivates of formula I as xitix reliable, general, effectively the source is used for people's tissue.Behind the in-situ hydrolysis, for example be present in in-house enzymic hydrolysis as skin after, they can be used as carboxylic acid sources or amino acid source and use.
According to the present invention, R 2For ammonium maybe can be selected from any suitable monovalence, divalence or tervalent metallic cation.
In an embodiment preferred of the present invention, R 2Be ammonium or Na for example +, K +Or Li +The monovalence metallic cation.In another embodiment of the invention, R 2Be the alkaline earth metal cation of divalence Mg for example ++, Ca ++Or Ba ++, or trivalent metal cation Al for example +++Or Fe +++In preferred embodiments, R 2Be selected from Na +, K +, Mg ++Or Ca ++
Term " C used herein 2-C 22Acyl group " refer to derive from carboxyl acyl group (carboxylic acyl) straight or branched, saturated or undersaturated carboxylic acid, such as but not limited to acetate, propionic acid, butanic acid, isopropylformic acid, Sorbic Acid, positive valeric acid, isovaleric acid, caproic acid, sad, capric acid, undeeanoic acid, laurostearic acid, tridecylic acid, TETRADECONIC ACID, pentadecanoic acid, palmitinic acid, hexadecylenic acid, stearic acid, oleic acid, linolic acid, linolenic acid, nonadecanoic acid and arachidonic acid.In a preferred embodiment, acyl group is C 8-C 18Acyl group, more preferably decoyl or palmityl.
Term " C used herein 1-C 17Alkyl " refers to the straight or branched alkyl; such as but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl, 2,2-dimethyl propyl, 1-ethyl propyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, n-undecane base, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl and n-heptadecane base.
Term used herein " amino acid " refers to natural or non-natural amino acid, and preferred natural a-amino acid is glycine, L-Ala, Serine, leucine, Isoleucine, phenylalanine, tyrosine, L-glutamic acid etc. for example.In a preferred embodiment, amino acid is glycine.
For making this compound as the use of biology available xitix source, preferably R 1, R 3And R 4For independently being selected from the part that is fit on natural and the physiology separately, for example come self-saturating and undersaturated fatty acid residue or from the part of amino-acid residue.
In some purposes, in order to reach the free ascorbic acid of relative high percent in the tissue after the hydrolysis, it is quite low that the molecular weight of compound of Formula I should keep.Therefore, in a preferred embodiment, R 3And R 4Be hydrogen, although preferred optional, because these group quite stable 5-hydroxyls and 6-hydroxyl do not need derivatize, and derivatize may unnecessarily increase the molecular weight of ascorbic acid derivates.This increase of molecular weight can reduce the free ascorbic acid amount of per unit weight in the compound.Yet this increase of molecular weight sometimes can be favourable.
Therefore, in an embodiment preferred of the present invention, R 3And R 4Be hydrogen, R 2Be ammonium, the monovalence metallic cation is Na for example +Or K +, or divalent alkaline-earth metal positively charged ion Mg for example ++Or Ca ++, R 1For deriving from C 6-C 22, preferred C 8-C 18, saturated or unsaturated lipid acid acyl group.In a preferred embodiment, R 1Be decoyl.In another preferred embodiment, R 1Be palmityl.
The for example hydrolysis easily in the skin cells of enzyme in the tissue, such ascorbic acid derivates of the present invention and all hydrolysates all are naturally occurring compounds, and therefore physiologic meaning can be arranged.In addition, they have middle polarity and therefore are dissolvable in water in aqueous medium and the lipophilic medium.
According to a further aspect in the invention, provide the method for synthesis type (1) compound, having comprised:
(a) pass through xitix and general formula R 7R 8The ketone one of CO protection 5 ' and 6 ' hydroxyl, the wherein R that react 7And R 8Identical or different, C respectively does for oneself 1-C 10Alkyl, the compound of generation general formula (II):
Figure A20048001650200121
(b) with the xitix molecule and the general formula R of the protection of the formula (II) of gained 1Hal compound one reacts, wherein R 1As above-mentioned definition, and if be that its amino of amino-acid residue is protected, produce the compound of general formula (III):
Figure A20048001650200131
(c) formula (III) compound and metal R 2Dense carbonate solution one react, produce the compound of general formula (IV):
(d) hydrolyzing type (IV) compound produces the compound of general formula (I), wherein R with deprotection 5-hydroxyl and 6-hydroxyl 3And R 4Be hydrogen.
The hydrolysis of formula (IV) compound is preferably carried out under mild conditions.5 and/or 6 derivatizes if desired; 2 of the first step protections and 3 s' hydroxyl; second 5 of the steps and/or 6 hydroxyl etherificates or esterification; the 3rd step 2 and 3 hydroxyl deprotections; then and suitable reagent 5 and/or 6 hydroxyls of acyl chlorides derivatize for example; thereby the formula of obtaining (I) compound, wherein R 3And/or R 4Not hydrogen.
The novel cpd of formula of the present invention (I) can be used to represent all known application and with found stable ascorbic acid derivates, be used for xitix as the xitix source and have in treatment, the nutrition or the active illness in the beauty treatment, disease and disorderly treatment.Therefore, new derivatives of the present invention is suitable for being used as the composition that composition comprises makeup, cosmeceutical (cosmeticeutical), nutrient supplement food (nutraceutical) and medicinal compositions, as unique activeconstituents or together with other activeconstituentss.
In one embodiment, the invention provides the compound that comprises formula (I) and the medicinal compositions of pharmaceutically acceptable carrier.These medicinal compositionss can be used for all illnesss, disease and the disorder that xitix wherein has therapeutic activity, for example use separately or with other reagent for example Thioctic Acid (as US 6,448,287 is described) or conventional chemotherapy agent coupling treatment cancer, perhaps antiscorbutic hypovitaminosis C perhaps is used for stimulating immune system.
In another embodiment, the invention provides the cosmetic composition that comprises carrier, vehicle or thinner that formula (I) compound and makeup are suitable for.These compositions can be applied topically to skin care, for example reduce microgroove (fine lines), wrinkle, pachylosis, be used for skin whitening and stimulate collagen synthetic as antidotal agent.
Cosmetic composition of the present invention or dermatological compositions can be used for treating the skin of skin lesion of radiation-induced property or photodamaged, especially the skin lesion of ultraviolet radiation-induced property, sunburn for example, be used for the skin lesion of long-term exposure under sight and the skin lesion of weather aging process, wherein relate to free radical damage and collagen content and reduce.
Therefore, the present invention also relates to the method for skin care, in particular for reducing microgroove, wrinkle, pachylosis, be used to make skin whitening or be used to stimulate the mammiferous collagen that these needs are arranged synthetic, this method comprises that topical administration has the described Mammals of needs to comprise the compound compositions of general formula of the present invention (I).
In one embodiment, composition of the present invention is the medicinal and cosmetic topical composition that is used for skin.These cosmetic compositions and dermatological compositions can effectively be sent vitamins C to skin.Comprise the cosmetic composition of stable ascorbic acid derivates of formula (I) and dermatological compositions and can be used as the emulsifiable paste of preserving moisture, anti-ageing emulsifiable paste, crease-resistant emulsifiable paste, sunscreen and be used to stimulate collagen synthetic etc., separately or with for example extract coupling of vitamin-E, vitamin P, Vogan-Neu, retinol ester, hyaluronic acid and/or algae of other activeconstituentss.
This composition can be made into various forms, includes but not limited to lotion, emulsifiable paste, gel, ointment, ointment, liquid etc.The performance of this preparation can change according to the purpose purposes consistent with the overall polarity of formula (I) compound.For example, the polar compound of formula (I) can be made into aqueous preparation example gel, and the more hydrophobic compound of formula (I) will be made the emulsion form.This topical composition will comprise carrier and vehicle, and for example water, emulsifying agent, natural oils, fat, antioxidant, stablizer, moistening agent, gelling form any other vehicle of agent, sanitas and cosmetic or dermatology purpose well known in the art.
Cosmetic composition of the present invention can comprise that also for example, carrier includes but not limited to water or ethanol; Wetting agent includes but not limited to glycerine; Buffer reagent includes but not limited to citric acid and Trisodium Citrate; Viscosity modifier includes but not limited to carbomer gel agent (carbomer gellingagents), Gum derivatives etc.; Sanitas includes but not limited to Tegosept M, propylben and phenoxyethyl alcohol; Emulsifying agent comprises but is not limited to tween 80 and glyceryl SUNSOFT Q-182S; Conditioning agent includes but not limited to oxystearic acid octyl group ester; Softener includes but not limited to cholesterol NF, Vaseline; Mineral oils and ester class include but not limited to tetradecanoic acid isopropyl esters, palmitinic acid isopropyl esters, 1-decene polymkeric substance (hydrogenation) and C 12-C 15Alkyl benzoate; Antioxidant includes but not limited to antioxidant BHT, tocopherol acetate etc.; The UV stablizer; UV radiation adsorber (sun-proof filter sunscreen filters); Flavouring agent; Tinting material; Or any aforesaid any combination.In addition, medicinal compositions of the present invention or nutrient supplement food composition also can with pharmaceutically effectively carrier make oral form, be used for all and need replenish the ascorbic situation that gives, the situation that comprises hypovitaminosis C, the perhaps essential situation that increases the vitamins C amount with the enhancing immunity system, perhaps vitamins C can help its any other situation.
The optional nutrient supplement food that comprises other of this nutrient supplement food composition is such as but not limited to VITAMIN, amino acid, hormone, prohormone and mineral substance according to the present invention.
Be oral administration, compound of the present invention can be made into capsule, tablet or liquid agent.For example, this activeconstituents mixes with the carrier with essential compression property in the tablet, and is compressed into required shape and size.Solid carrier comprises, for example calcium phosphate, Magnesium Stearate, talcum powder, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine and poly-(vinyl pyrrolidone).Liquid preparation can be made into solution, suspension, emulsion or syrup and uses.This activeconstituents is dissolvable in water or is suspended in the pharmaceutically acceptable liquid solvent, for example the mixture of water, organic solvent and pharmaceutically acceptable oils or fat.The suitable liquid vehicle of oral administration comprises water, pure and mild oils.Said composition can microcapsule or nanocapsule form sealing The compounds of this invention.
Now be that example has been illustrated the present invention with the following non-limiting examples.
Embodiment
Synthesizing of embodiment 1.2-decoyl SODIUM ASCORBATE
Step 1. 5,6-isopropylidene (isopropylidenyl) xitix synthetic
The anhydrous cupric sulfate that adds 20g (0.125mol) in the 660mL anhydrous propanone suspension of xitix (20g (0.114mol)) stirs this reaction mixture 20h under the room temperature.Monitor this process with TLC (chloroform-methanol-water, 10: 10: 3).Obtain 5 of 22.57g (92%), 6-isopropylidene xitix after filtration and the evaporation.
Step 2.2-decoyl-5,6-isopropylidene xitix synthetic.
To 5,6-isopropylidene xitix (14.5g, in anhydrous pyridine 0.067mol) (80mL) solution, in 0 ℃ drip capryl(yl)chloride (12.0g, 0.074mol).0 ℃ is stirred this reactive system 1.5h down, and monitors this process with TLC (chloroform-methanol, 3: 1).Then, add frozen water (300mL) and with phosphoric acid (～10mL) transfer this reaction mixture pH value to 3, and with ethyl acetate (2 * 100mL) extractions.The extracting solution that merges with the saturated nacl aqueous solution washing is 7 up to pH.Organic layer and the vacuum concentration washed with anhydrous magnesium sulfate drying.With hexane wash residue and vacuum concentration to the 2-decoyl-5 that obtains 22.9g (89%), 6-isopropylidene xitix.
Step 3.2-decoyl-5,6-isopropylidene SODIUM ASCORBATE synthetic
3.0g 2-decoyl-5,6-isopropylidene dissolution of ascorbic acid is in the ethyl acetate of 150mL and place separatory funnel.The 3M sodium carbonate solution that adds 50mL in the solution that makes.Mix the back and place about 10min, obtain a kind of three-phase system.Choose intermediate phase, filter and concentrate.The productive rate of end product equals 65-70%.Obtain 2-decoyl-5, the unformed material of lurid solid of 6-isopropylidene SODIUM ASCORBATE.
Synthesizing of step 4.2-decoyl SODIUM ASCORBATE.
The 5-hydroxyl of the compound of step 3 and 6-hydroxyl deprotection obtain end product, under mild conditions, 4 ℃, utilize reaction mixture MeOH: H 2O: 2N HCl=30: 2: 1 (v/v/v), continue 24h, to wash up to pH 7 with sodium-chlor then, product vacuum-drying completely is to remove organic solvent.Productive rate: about 90%.
Synthesizing of embodiment 2. 2-palmityl SODIUM ASCORBATE
Step 1. 5,6-isopropylidene xitix synthetic
The anhydrous cupric sulfate that adds 20g (0.125mol) in the 660mL anhydrous propanone suspension of the xitix of 20g (0.114mol) stirs this reaction mixture 20h under the room temperature.Monitor this process with TLC (chloroform-methanol-water, 10: 10: 3).Obtain 5 of 22.57g (92%), 6-isopropylidene xitix after filtration and the evaporation.
Step 2.2-palmityl-5,6-isopropylidene xitix synthetic
To 5,6-isopropylidene xitix (14.5g, in anhydrous pyridine 0.067mol) (80mL) solution, 0 ℃ drip palmityl chloride (12.0g, 0.074mol).0 ℃ is stirred this reactive system 1.5h down, and monitors this process with TLC (chloroform-methanol, 3: 1).Then, add frozen water (300mL) and with phosphoric acid (～10mL) transfer this reaction mixture pH value to 3, and with ethyl acetate (2 * 100mL) extractions.The extracting solution that merges with the saturated nacl aqueous solution washing is 7 up to pH.Organic layer and the vacuum concentration washed with anhydrous magnesium sulfate drying.Hexane wash residue and vacuum concentration obtain the 2-palmityl-5 of 22.9g (89%), 6-isopropylidene xitix.
Step 3. 2-palmityl-5,6-isopropylidene SODIUM ASCORBATE synthetic
3.0g 2-palmityl-5,6-isopropylidene dissolution of ascorbic acid is in the ethyl acetate of 150mL and place separatory funnel.The 3M sodium carbonate solution that adds 50mL in the solution that makes.Mix the back and place about 10min, obtain a kind of three-phase system.Choose intermediate phase, filter and concentrate.The productive rate of end product equals 65-70%.Obtain 2-palmityl-5, the unformed material of lurid solid of 6-isopropylidene SODIUM ASCORBATE.
Synthesizing of step 4. 2-palmityl SODIUM ASCORBATE.
The 5-hydroxyl of the compound of step 3 and 6-hydroxyl deprotection obtain end product, and mild conditions, utilizes reaction mixture MeOH: H by 4 ℃ 2O: 2N HCl=30: 2: 1 (v/v/v), continue 24h, to wash up to pH 7 with sodium-chlor then, product vacuum-drying completely is to remove organic solvent.Productive rate: about 90%.
As the same approach that embodiment 1-2 describes, when being K, Ca or Mg, metal obtains other compound, and for example 2 esters are from other carboxylic acid, preferred fatty acid, or from amino acid for example glycine or L-Ala.
Embodiment 3: dermatology effect-ascorbic acid derivates stimulates the interior collagen of initial stage human foreskin fibroblast synthetic
The L-xitix stimulates the interior collagen of (cultured) human skin fibroblast of cultivating synthetic.Ascorbate salt helps several metabolic processes to comprise the available hydroxylization of the synthetic middle oxyproline of collagen.
In order to estimate ascorbic acid derivates of the present invention to collagen synthetic effect, the human foreskin fibroblast of cultivating to be put in the little culture plate in 24-hole (microculture plates), substratum is for containing 100 μ g/ml β-An Jibingjing, 10 μ Ci[2,3- 3H] DMEM that is supplemented with 10% foetal calf serum of proline(Pro), wherein there are the xitix (positive control) of different concns or the ascorbic acid derivates of embodiment 1 or 2, for example from 1mM to 50mM.Culture was hatched 24 hours.Measure [2,3- 3H]-proline(Pro) mixes the situation of the extracellular collagen of the sedimentary antipepsin of salt, and is used as collagen synthetic efficiency index.The result is the mean number in four same treatment holes and counts correction with sample cell.The expection ascorbic acid derivates shows suitable with the L-xitix or better collagen synthetic effect.

Claims (31)

1. the compound of a general formula I:
R wherein 1Be C 2-C 22Acyl group, amino acid group or C 1-C 17Alkyl; R 2Be ammonium or metallic cation; And R 3Or R 4Independent separately is hydrogen, C 2-C 22Acyl group, amino-acid residue or C 1-C 17Alkyl.
2. the compound of claim 1, wherein R 2For ammonium or be selected from Na +, K +Or Li +The monovalence metallic cation.
3. the compound of claim 1, wherein R 2For being selected from Mg ++, Ca ++Or Ba ++The divalent alkaline-earth metal positively charged ion or be selected from Al +++Or Fe +++Trivalent metal cation.
4. the compound of claim 1, wherein R 2Be selected from Na +, K +, Mg ++Or Ca ++
5. the compound of claim 1, wherein R 1For deriving from C straight or branched, saturated or undersaturated carboxylic acid 2-C 22Carboxyl acyl group, described carboxylic acid are selected from acetate, propionic acid, butanic acid, isopropylformic acid, Sorbic Acid, positive valeric acid, isovaleric acid, caproic acid, sad, capric acid, undeeanoic acid, laurostearic acid, tridecylic acid, TETRADECONIC ACID, pentadecanoic acid or arachidonic acid.
6. the compound of claim 5, wherein R 1Be C 8-C 18Acyl group.
7. the compound of claim 6, wherein R 1Be decoyl or hexadecanoyl.
8. the compound of claim 1, wherein R 1Be natural a-amino acid residue, for example glycine, L-Ala, Serine, leucine, Isoleucine, phenylalanine, tyrosine or glutaminic acid residue.
9. the compound of claim 1, wherein R 1Be glycine residue.
10. the compound of claim 1, wherein R 3And R 4Be hydrogen, R 2Be ammonium or metallic cation, R 1For deriving from the C of lipid acid 8-C 18Acyl group.
11. the compound of claim 10, wherein R 2For being selected from Na +, K +Or Li +The monovalence metallic cation or be selected from Mg ++Or Ca ++Divalent metal.
12. the compound of claim 1, wherein R 3And R 4Be hydrogen, R 2Be Na +, R 1Be decoyl.
13. the compound of claim 1, wherein R 3And R 4Be hydrogen, R 2Be Na +, R 1Be hexadecanoyl.
14. a composition, it comprises as each compound among the claim 1-13 of activeconstituents.
15. the medicinal compositions of claim 14 is used for the treatment of illness, disease or disorder that relevant with hypovitaminosis C and/or vitimin supplement C may be useful.
16. the medicinal compositions of claim 14 is used for the treatment of cancer.
17. the medicinal compositions of claim 16 also comprises Thioctic Acid or chemotherapeutics.
18. the medicinal compositions of claim 15 is used for the enhancing immunity system.
19. the nutrient supplement food composition of claim 14, the optional nutrient supplement food that comprises other.
20. claim 14 be suitable for oral medicinal or nutrient supplement food composition, formula (I) compound of optional form sealing significant quantity with microcapsule/nanocapsule.
21. the medicinal compositions of claim 14 uses for local.
22. the cosmetic composition of claim 14 also contains carrier, vehicle or thinner that makeup are suitable for.
23. the cosmetic composition of claim 22 is applied topically to skin care.
24. the cosmetic composition of claim 23 is used to reduce microgroove, wrinkle or pachylosis, makes skin whitening or stimulates collagen synthetic.
25. the cosmetic composition of claim 24 uses as antidotal agent.
26. the cosmetic composition of claim 24 is used for the treatment of the skin of photodamaged.
27. the cosmetic composition of claim 22, form are washing lotion, emulsifiable paste, gel or liquid form.
28. the cosmetic composition of claim 22 uses as the emulsifiable paste of preserving moisture, anti-ageing emulsifiable paste, crease-resistant emulsifiable paste, sunscreen, makes skin whitening and is used to stimulate collagen synthetic.
29. the cosmetic composition of claim 22 also comprises for example extract of vitamin-E, vitamin P, Vogan-Neu, retinol ester, hyaluronic acid and/or algae of one or more activeconstituentss.
30. the dermatological compositions of claim 14 is used for the treatment of or control is relevant with hypovitaminosis C and/or vitimin supplement C may be useful skin condition or illness.
31. the method for a skin care, in particular for reducing microgroove, wrinkle and pachylosis, or being used to stimulate the mammiferous collagen synthetic skin care method that these needs are arranged, described method comprises that topical administration has the described Mammals of needs to comprise the compound compositions of the general formula (I) of claim 1.
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CN103896891A (en) * 2014-03-25 2014-07-02 李玉成 Ascorbic acid lithium and preparation method thereof
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CN113527537A (en) * 2021-07-14 2021-10-22 润辉生物技术（威海）有限公司 Levo-vitamin C hyaluronic acid ester derivative and preparation method and application thereof

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CN103655223A (en) * 2013-11-14 2014-03-26 陕西东大生化科技有限责任公司 Preparation with effects of preventing and treating acnes and application thereof
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CN103896891A (en) * 2014-03-25 2014-07-02 李玉成 Ascorbic acid lithium and preparation method thereof
CN110467689A (en) * 2019-09-09 2019-11-19 山东众山生物科技有限公司 A kind of derivatives of hyaluronic acids and preparation method thereof
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